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Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity
Scott R. Walsh, … , John C. Bell, Yonghong Wan
Scott R. Walsh, … , John C. Bell, Yonghong Wan
Published November 13, 2018
Citation Information: J Clin Invest. 2019;129(2):518-530. https://doi.org/10.1172/JCI121004.
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Research Article Autoimmunity Article has an altmetric score of 12

Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity

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Abstract

Despite its success in treating melanoma and hematological malignancies, adoptive cell therapy (ACT) has had only limited effects in solid tumors. This is due in part to a lack of specific antigen targets, poor trafficking and infiltration, and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVVs) to drive expansion and tumor infiltration of transferred antigen-specific T cells and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequences when the antigen targeted was a self-protein. However, modulation of IFN-α/-β signaling, either by functional blockade or rational selection of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFN-α/-β in facilitating autoimmune toxicity during cancer immunotherapy and presents a safe and powerful combinatorial regimen with immediate translational applications.

Authors

Scott R. Walsh, Donald Bastin, Lan Chen, Andrew Nguyen, Christopher J. Storbeck, Charles Lefebvre, David Stojdl, Jonathan L. Bramson, John C. Bell, Yonghong Wan

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Figure 6

B18R-mediated neutralization of IFN-α/-β decouples tumor regression from autoimmune diabetes but can be overwhelmed by pIC treatment.

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B18R-mediated neutralization of IFN-α/-β decouples tumor regression from...
(A) Systemic levels of IFN-α and IFN-β detected in plasma samples taken from B16-gp33 tumor–bearing RIP-gp mice at the indicated time point (hours post infection [hpi]) after injection of the VSV-gp33 (n = 4), VacV-gp33 (n = 6), or VacVΔB18R-gp33 (n = 5) component of the combination therapy. (B) gp33-specific CD8+ T cell responses and (C) tumor volume were measured on the indicated dpi in B16-gp33 tumor–bearing RIP-gp mice treated with P14 TCM cells plus VacV-gp33 (n = 5) or P14 TCM cells plus VacVΔB18R-gp33 (n = 4). (D) Percentage of mice that developed diabetes. (E) Systemic levels of IFN-α and IFN-β in plasma samples (n = 5), (F) gp33-specific CD8+ T cell responses, and (G) tumor volume induced by the combination therapy were measured on the indicated day following infection with VacV-gp33 (n = 4). This was followed by pIC treatment on day 5 after infection (120 hpi), as shown by the black arrows in E, G and H (n = 5). An additional group received a bolus of the IFNAR-blocking Ab 2 hours prior to pIC treatment, as shown by the gray arrow in G and H (n = 5). (H) Percentage of mice that developed diabetes. Data for B–D and F–H are representative of 2 independent experiments and are shown as the mean ± SD. *P < 0.05, **P < 0.01, and ****P < 0.0001, by 2-way ANOVA (A and F) or 1-way ANOVA (E) with Holm-Sidak correction for multiple comparisons, 2-tailed Student’s t test (B), and log-rank (Mantel-Cox) test (D and H).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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